Autism spectrum disorder profile in neurofibromatosis type I.

Neurofibromatosis Type 1 (NF1) is a common autosomal dominant single-gene disorder, in which the co-occurrence of autism spectrum disorder (ASD) has attracted considerable research interest recently with prevalence estimates of 21-40%. However, detailed characterization of the ASD behavioral phenotype in NF1 is still lacking. This study characterized the phenotypic profile of ASD symptomatology presenting in 4-16 year old children with NF1 (n = 36) using evidence from parent-rated Social Responsiveness Scale and researcher autism diagnostic observation Scale-2. Compared to IQ-matched reference groups of children with autism and ASD, the NF1 profile shows overall similarity but improved eye contact, less repetitive behaviors and better language skills.

The social behavioral phenotype in boys and girls with an extra X chromosome (Klinefelter syndrome and Trisomy X): a comparison with autism spectrum disorder.

The present study aimed to gain more insight in the social behavioral phenotype, and related autistic symptomatology, of children with an extra X chromosome in comparison to children with ASD. Participants included 60 children with an extra X chromosome (34 boys with Klinefelter syndrome and 26 girls with Trisomy X), 58 children with ASD and 106 controls, aged 9 to 18 years. We used the Autism Diagnostic Interview, Social Responsiveness Scale, Social Anxiety Scale and Social Skills Rating System. In the extra X group, levels of social dysfunction and autism symptoms were increased, being in between controls and ASD. In contrast to the ASD group, the extra X group showed increased social anxiety. The effects were similar for boys and girls with an extra X chromosome.

Early detection of chromosome 9q22.32q31.1 microdeletion and the nevoid basal cell carcinoma syndrome.

We report on a patient with a microdeletion of chromosome region 9q22.32q31.1 including the PTCH1 gene (human homologue of the Drosophila patched 1 gene), review the findings in the reported patients with similar array CGH findings, and highlight the non nevoid basal cell carcinoma/non-Gorlin syndrome findings at an earlier age. These are macrocephaly, neonatal hypotonia, severe psychomotor retardation with markedly delayed motor milestones and speech development, epicanthic folds, a thin upper lip, a short and wide/webbed neck, pectus excavatum and (kypho)scoliosis. These features should alert the physician to an early diagnosis of the microdeletion and allow the initiation of essential clinical management hereof.

X-linked mental retardation, short stature, microcephaly and hypogonadism maps to Xp22.1-p21.3 in a Belgian family.

X-linked mental retardation (XLMR) is a heterogeneous disorder that can be classified as either non-specific (MRX), when mental retardation is the only feature, or as syndromic mental retardation (MRXS). Genetic defects underlying XLMR are being identified at a rapid pace, often starting from X-chromosomal aberrations and XLMR families with a well-defined linkage interval. Here, we present a new family with a syndromic form of XLMR, including mild mental retardation, short stature, microcephaly and hypogonadism. Two-point linkage analysis with 24 polymorphic markers spanning the entire X chromosome was carried out. We could assign the causative gene to a 6 cM interval in Xp22.1-p21.3, with a maximum LOD score of 2.61 for markers DXS989 and DXS1061 at theta = 0.00. No mutations were found in the presented family for two known MRX genes mapping to this interval, ARX and IL1RAPL-1. These data indicate that the interval Xp22.1-p21.3 contains at least one additional MRXS gene.

Screening for FMR-1 premutations in 122 older Flemish males presenting with ataxia.

Recently, Hagerman et al described the occurrence of a late-onset neurological disorder in five male carriers of the fragile-X (FMR-1) premutation. The major characteristics of this disorder, designated the Fragile-X Tremor Ataxia Syndrome (FXTAS), are progressive intention tremor, cerebellar ataxia and cognitive decline. Most cases of FXTAS published thus far were ascertained through families with a known fragile-X proband. Since cerebellar ataxia is one of the main cardinal features, we performed FMR-1 premutation screening in 122 male patients, older than 50 years, who were referred to us for testing of the spinocerebellar ataxia (SCA 1, 2, 3, 6, 7) genes and who were found to be negative. In this group of patients, we found five patients with an FMR-1 premutation. In four of them, a definite diagnosis of FXTAS could be made, based on the proposed diagnostic clinical and radiological criteria for FXTAS. In light of these figures, we recommend that FMR-1 analysis should be included in the molecular diagnostic work-up in the group of male ataxia patients older than 50 years.

Inv(X)(p21.1;q22.1) in a man with mental retardation, short stature, general muscle wasting, and facial dysmorphism: clinical study and mutation analysis of the NXF5 gene.

We describe a 59-year-old male (patient A059) with moderate to severe mental retardation (MR) and a pericentric inversion of the X-chromosome: inv(X)(p21.1;q22.1). He had short stature, pectus excavatum, general muscle wasting, and facial dysmorphism. Until now, no other patients with similar clinical features have been described in the literature. Molecular analysis of both breakpoints led to the identification of a novel "Nuclear RNA export factor" (NXF) gene cluster on Xq22.1. Within this cluster, the NXF5 gene was interrupted with subsequent loss of gene expression. Hence, mutation analysis of the NXF5 and its neighboring homologue, the NXF2 gene was performed in 45 men with various forms of syndromic X-linked MR (XLMR) and in 70 patients with nonspecific XLMR. In the NXF5 gene four nucleotide changes: one intronic, two silent, and one missense (K23E), were identified. In the NXF2 gene two changes (one intronic and one silent) were found. Although none of these changes were causative mutations, we propose that NXF5 is a good candidate gene for this syndromic form of XLMR, given the suspected role of NXF proteins is within mRNA export/transport in neurons. Therefore, mutation screening of the NXF gene family in phenotypically identical patients is recommended.

A distinct neurocognitive phenotype in female fragile-X premutation carriers assessed with visual attention tasks.

Premature ovarian failure (POF) and underlying hormonal changes are recognized as a distinct phenotype in female fragile-X premutation carriers. Neurocognitive deficits, in particular mental retardation, are associated with the full mutation in males and females. In female full mutation carriers this neurocognitive phenotype is expressed more mildly than in males. Research on whether the fragile-X premutation is associated with a particular neurocognitive phenotype or not has been equivocal. By means of the Sonneville Visual Attentions Tasks (SVAT) computer-based battery of neurocognitive tasks, we assessed reaction time on different tasks in three groups of subjects: female premutation carriers, female full mutation carriers, and female control subjects. The results show that a fraction of the female premutation carriers perform poorly on several selective attention tasks, but not on other tasks. Their neurocognitive profile is different from that of control subjects and of the majority of female premutation carriers. It may also be different from the phenotype of female full mutation carriers, though in that respect this study remains inconclusive. These findings support earlier findings that the fragile-X premutation may affect neurocognitive functioning, in particular aspects of attention.

Clinical study and haplotype analysis in two brothers with Partington syndrome.

Partington et al. [1988] described a three-generation family (MRXS1, MIM *309510, PRTS) with a syndromic form of X-linked mental retardation (XLMR). The clinical features in 10 affected males included mild to moderate MR, dystonic movements of the hands, and dysarthria. After refinement, the PRTS locus was mapped to marker DXS989 (with maximum LOD score of 3.1) with flanking markers DXS365 and DXS28. Since then, no other patients with a similar phenotype have been described. We present a detailed description of the neurological symptoms and the disease history of two brothers with the clinical features of PRTS. Psychomotor development was delayed in both, and neurological features included mild to moderate mental retardation, dysarthria, facial muscle weakness, severe dysdiadochokinesis, slow dystonic movements, and mild spasticity of the hands, without ataxia or spasticity of the legs. The symptoms were nonprogressive and extrapyramidal, and without cerebellar involvement. In general, behavior of the two brothers was friendly and quiet, although the elder brother had periods of depressed mood and outbursts of anger. Karyotypes and subsequent investigation of the subtelomeres as well as DNA analysis of the FMR1 gene, the androgen receptor gene, and the DM locus did not reveal a genetic abnormality. Haplotype analysis showed that the affected brothers share the PRTS region at Xp22.1. Mutation screening of the PDH-E1alpha gene did not reveal a pathogenic mutation.